tbuckley/cabot-search huggingface dataset:
Abstract 3500: A noncatalytic role for mettl1 in oncogenic translation in soft tissue sarcoma
Authors: Raja Hussain Ali, Brianna Silverman, Esteban A. Orellana, Alyssa Kennedy, Caitlin Bowers, Ashley Gutierrez, David Papke, Christopher D. Fletcher, Antonio P. Atayde, Akiko Shimamura, Richard I. Gregory, Alejandro Gutierrez
Journal: Cancer Research (2023)

Abstract Amplification of chromosomal material derived from 12q is pathognomonic in a subset of soft tissue sarcomas (STS), including well-differentiated and dedifferentiated liposarcoma. However, it remains unclear which of the amplified genes are oncogenic drivers, obstacles to rational therapeutic development. We defined a minimal 12q amplicon in human liposarcoma, and tested the oncogenic activity of each recurrently amplified gene to accelerate the onset of AKT-induced STS in a genetically engineered zebrafish model of the disease. This revealed several genes whose overexpression accelerated the onset of AKT-induced STS, including METTL1, best-known for its ability to catalyze methylation of tRNAs. Surprisingly, catalytically defective mutants of METTL1 exhibited oncogenic activity that was at least as potent as the wild-type gene in zebrafish and human STS, indicating enzyme-independent oncogenic functions. We found that METTL1 promotes ribosome assembly and oncogenic translation independent of its enzymatic activity. In human liposarcoma cells and mouse embryonic fibroblasts, METTL1 overexpression was sufficient to stimulate polysome formation, and this effect was phenocopied by catalytically dead mutants of METTL1. METTL1 overexpression also robustly stimulated the rate of protein synthesis in cells (P &amp;lt; 0.0001), and in a cell-free biochemical assay for translation of a reporter mRNA (P &amp;lt; 0.001). The ability of METTL1 to stimulate ribosomal function triggered a therapeutically targetable dependency, because small molecule inhibitors of ribosome biogenesis had potent therapeutic activity against METTL1-amplified (P &amp;lt; 0.0001), but not METTL1 wild-type, sarcoma cells. Thus, METTL1 is a soft tissue sarcoma oncogene that stimulates oncogenic translation independent of its enzymatic activity, an oncogenic function that can be targeted therapeutically. Citation Format: Raja Hussain Ali, Brianna Silverman, Esteban A. Orellana, Alyssa Kennedy, Caitlin Bowers, Ashley Gutierrez, David Papke, Christopher D. Fletcher, Antonio P. Atayde, Akiko Shimamura, Richard I. Gregory, Alejandro Gutierrez. A noncatalytic role for mettl1 in oncogenic translation in soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3500.
Abstract 5912: Bitter taste receptors link between microbiome dysbiosis and programmed cell death in oral squamous cell carcinoma
Authors: Byeong-Oh Hwang, Se-Young Park, Na-Young Song
Journal: Cancer Research (2023)

Abstract Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancers. It has been reported that the composition of the oral microbiome was shifted in OSCC patients compared to healthy subjects. In particular, Pseudomonas aeruginosa was enriched in the oral cavity of OSCC patients. Bitter taste receptors (taste 2 receptors, TAS2Rs), known as G protein-coupled receptors (GPCRs), can recognize quorum sensing molecules, such as N-(3-oxododecanoyl)-L-homoserine lactone (oxo-C12) secreted from P. aeruginosa. Based on The Cancer Genome Atlas analysis, downregulation of TAS2Rs was correlated with poor prognosis in various cancers. This prompted us to investigate the role of TAS2Rs in oral dysbiosis and cancers. Here, we found that TAS2Rs mediated both apoptosis and pyroptosis, distinct types of programmed cell death, in response to oxo-C12, in OSCC cell lines. Of note, it was blocked by knockdown of TAS2R4, 14, or 38. Unexpectedly, TAS2Rs-mediated apoptosis and pyroptosis were GPCR-independent. Given our observation that the blockade of NLRP3 inflammasome attenuated oxo-C12-induced OSCC cell death, TAS2Rs seem to recruit NLRP3 inflammasome rather than G protein signaling pathway in order to mediate the programmed cell death in OSCC. Once NLRP3 is activated, caspase-8 triggered both apoptosis and pyroptosis in response to oxo-C12, supporting the role of TAS2Rs-NLRP3-caspase-8 axis. Interestingly, siRNA knockdown of MyD88 diminished oxo-C12-induced programmed cell death, implying the possible involvement of MyD88 in the TAS2Rs-NLRP3-caspase-8 axis. Taken together, bitter taste receptors promote the programmed cell death of OSCC in response to oral dysbiosis through activation of NLRP3 inflammasome, which further supports TAS2Rs as prognostic markers in OSCC. Thus, these results will shed light on better understanding of interplay between microbiome and cancer, proposing TAS2Rs as novel therapeutic targets in oral dysbiosis-induced OSCC development. Citation Format: Byeong-Oh Hwang, Se-Young Park, Na-Young Song. Bitter taste receptors link between microbiome dysbiosis and programmed cell death in oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5912.
Abstract 4796: Chemotherapy induced senescence drives peripheral neuropathy
Authors: Taylor Malachowski, Ganesh Raut, Satarupa Mullick Bagchi, Shelia Stewart
Journal: Cancer Research (2023)

Abstract Chemotherapy is a mainstay of cancer therapy. Unfortunately, while chemotherapy can profoundly impact disease free survival, it’s often accompanied with devastating side effects, including peripheral neuropathy. Indeed, 30-40% of patients treated with neurotoxic chemotherapy develop long-term and often debilitating chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, there are currently no preventative measures for CIPN and while it is transitory in some patients, for others the side effects can persist for months or even years after the cessation of chemotherapy. Recent work suggests that cellular senescence, which is robustly induced by chemotherapy, contributes to CIPN. Senescent cells are typically characterized by increased CDKn2a (i.e., p16) expression, increased SA-β-gal hydrolyzation, and expression of the senescence-associated secretory phenotype (SASP) that can influence multiple cell types in the microenvironment. Through utilization of a mouse model that employs paclitaxel (PTX), we find that PTX robustly induces senescence in the hindpaws and dorsal root ganglia (DRG) of mice that display loss of peripheral axons and decreased response to mechanical stimuli. To address the role of senescence in CIPN, we utilized the INKATTAC mouse that allows for inducible elimination senescent cells. Using this model, we find that the elimination of senescent cells rescues CIPN. Further, the use of senolytics, drugs that kill senescent cells, also rescues CIPN, raising the possibility that we can treat patients with CIPN. To address the mechanism behind CIPN we have carried out single cell RNA-Seq to identify the population of senescent cells senescing in response to chemotherapy. These analyses will allow us to understand the mechanisms that drive CIPN and may lead to new treatments for patients suffering from CIPN. Citation Format: Taylor Malachowski, Ganesh Raut, Satarupa Mullick Bagchi, Shelia Stewart. Chemotherapy induced senescence drives peripheral neuropathy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4796.
Abstract 993: Epigenetic immune cell profiling in B-non-Hodgkin lymphoma biopsies
Authors: Jeannette Werner, Steffi Walter, Christoph Sachsenmaier, Janika Schulze, Deborah Phippard, Sven Olek, Barbara Seliger, Claudia Wickenhauser
Journal: Cancer Research (2023)

Abstract Early detection and differential diagnosis of Non-Hodgkin lymphoma (NHL) is essential for the initiation of suitable therapy options. Biopsy based diagnosis allows allocation to World Health Organization (WHO) sub-classification groups but prognosis often needs identification of specific genetic aberrations or gene expression patterns. Despite this strategy, prognosis is difficult, since diseases, like e.g. mantel cell lymphoma, can be indolent or aggressive. Here we report the characterization of NHL biopsies using epigenetic immune cell quantification. This approach is based on the identification of specifically demethylated regions in individual immune cell types. These regions are then quantified using methylation-sensitive qPCR after bisulfite conversion. This highly reproducible and objective method allows in depth immunophenotyping of the tumor microenvironment. Next to CD4+ and CD8+ T cells, B cells and NK cells more specialized immune cells like regulatory T cells (Tregs), follicular T helper cells, PD-1 expressing cells and Myeloid derived suppressor cells (MDSC) were quantitatively determined in formalin-fixed tissue samples of 251 patients with different B cell Non-Hodgkin lymphomas. As a result, characteristic immune cell distribution patterns were identified for the different lymphoma entities, including chronic lymphocytic leukemia (B-CLL) (n=41), mantle cell lymphoma (MCL) (n=32), follicular lymphoma (FL) (n=33), diffuse large B cell lymphoma (DLBCL) (n=74), marginal zone lymphoma (MZL) (n=40) and B cell acute lymphoblastic leukemia (B-ALL) (n=26). In addition, substantial heterogeneity within the entities was observed that may correlate with disease prognosis. Among others, this is particularly the case for MDSC in B-CLL patients as well as for NK cells and Tregs in MCL and PD-1+ cells in FL patients. Currently clusters within the different disease groups are analyzed with regard to the clinical outcome to investigate if disease prognosis can be predicted by epigenetic immune cell quantification. In conclusion, epigenetic immune cell quantification is a suitable method to analyze the tumor microenvironment of NHL patients with the potential to support patient’s prognosis. Citation Format: Jeannette Werner, Steffi Walter, Christoph Sachsenmaier, Janika Schulze, Deborah Phippard, Sven Olek, Barbara Seliger, Claudia Wickenhauser. Epigenetic immune cell profiling in B-non-Hodgkin lymphoma biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 993.
Abstract 4824: Intracellular ferritin expression levels regulate growth and resistance to ferroptosis in pancreatic cancer cell lines
Authors: Masataka Maruno, Yo-hei Kanamori, Takashi Matsumoto, Yuta Shiraishi, Toru Takematsu, Tatsunori Miyata, Kosuke Mima, Shigeki Nakagawa, Hidetoshi Nitta, Hiromitsu Hayashi, Toshiro Moroishi, Hideo Baba
Journal: Cancer Research (2023)

Abstract Background: Pancreatic cancer is one of the cancers with the highest mortality rate, and it is important to develop effective treatments and elucidate prognostic factors. It has been reported that elevated serum ferritin is associated with the prognosis of pancreatic cancer. However, there are few reports on how ferritin in pancreatic cancer tissue acts in pancreatic cancer. Ferritin heavy chain (FTH) is a major component of ferritin, which stores iron and plays a role in suppressing iron-induced generation of reactive oxygen species. In this study, we aimed to examine the expression level of FTH in pancreatic cancer cells and its prognostic and cell biological roles. Methods: We performed immunostaining of FTH in pancreatic cancer tissue specimens operated on at our hospital and classified the expression level of FTH by scoring the immunostaining intensity and staining rate. The expression levels and prognosis were then evaluated. The overexpression and knockout strains of FTH were generated using a human pancreatic cancer cell line (MIAPaCa-2), and their proliferative and stress tolerance abilities were compared with those of the control group. Results: Immunostaining of 149 pancreatic cancer surgical specimens showed that the group with high FTH had a significantly shorter overall survival rate than the group with low FTH (5-year survival rate; 16.8% vs. 36.9%, p = 0.018). In multivariate analysis, high FTH expression was also a prognostic factor: in vitro, cell lines overexpressing FTH had enhanced proliferative potential compared to controls, while knockout lines were suppressed. In addition, the knockout lines showed decreased resistance to RSL-3, an inducer of ferroptosis. Additional studies are currently underway to examine resistance to other drugs and the production of reactive oxygen species in the cells. Conclusion: In pancreatic cancer, high ferritin expression is associated with worse prognosis and may enhance cell proliferation and stress tolerance, and might be a new treatment or biomarker. Citation Format: Masataka Maruno, Yo-hei Kanamori, Takashi Matsumoto, Yuta Shiraishi, Toru Takematsu, Tatsunori Miyata, Kosuke Mima, Shigeki Nakagawa, Hidetoshi Nitta, Hiromitsu Hayashi, Toshiro Moroishi, Hideo Baba. Intracellular ferritin expression levels regulate growth and resistance to ferroptosis in pancreatic cancer cell lines. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4824.
Abstract 515: Discovery of potent and orally available small molecule inhibitors of the SOS1-KRAS interaction
Authors: Ha Na Yu, Dong Hyuk Ki, Joonwoo Nam, Eun-Jung Kim, Sungeun Kim, Hunmi Choi, Jieun Kim, Jihyun Yu, Donggeon Kim, Dohyun Park, Kyeong Jin Yoon, Seongin Jo, So-Hyeon Hwang, Sang Kyun Lim, Young Sook Shin, Wooseok Han
Journal: Cancer Research (2023)

Abstract Abnormal activating mutation of KRAS is frequently found in many human cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). KRAS activating mutations lead to hyperactivation of the MAPK/ERK signaling pathway, resulting in promotion of cell proliferation and growth. SOS1 is one of the major guanine nucleotide exchange factors (GEFs) that regulates RAS proteins including KRAS. Since SOS1 plays a critical role in converting the GDP-bound inactive KRAS “off” state to the GTP-bound active KRAS “on” state, disruption of SOS1 and KRAS protein-protein interaction would be effective to block KRAS-driven oncogenic signaling regardless of its mutation status. Importantly, SOS1 activity is crucial during the reactivation of the KRAS/MAPK signaling upon the treatment of RAS/MEK/ERK inhibitors, thus a SOS1 inhibitor would be an effective therapeutic option to treat KRAS-driven tumors in combination with RAS pathway inhibitors. We developed potent, selective, and orally available small molecules that effectively disrupt the interaction between SOS1 and KRAS. Current lead compounds originated from a virtual screening displayed excellent ADME and PK profiles. In cellular assays, a robust reduction of phospho-ERK level and cancer cell growth were shown. We also observed excellent in vivo antitumor activity in the mouse xenograft models. Moreover, combination with Sotorasib synergistically inhibited tumor cell growth both in vitro and in vivo. Overall, our SOS1 inhibitors demonstrate great therapeutic potential for cancer patients with KRAS mutations. Citation Format: Ha Na Yu, Dong Hyuk Ki, Joonwoo Nam, Eun-Jung Kim, Sungeun Kim, Hunmi Choi, Jieun Kim, Jihyun Yu, Donggeon Kim, Dohyun Park, Kyeong Jin Yoon, Seongin Jo, So-Hyeon Hwang, Sang Kyun Lim, Young Sook Shin, Wooseok Han. Discovery of potent and orally available small molecule inhibitors of the SOS1-KRAS interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 515.
Abstract 2227: Streamlined workflow for analyzing and reporting hematological malignancies in Bionano VIATM software
Authors: Benjamin Clifford, Jen Hauenstien, Andy Wing Chun Pang, Rachel D. Burnside, Neil Miller, Alex Hastie, Alka Chaubey
Journal: Cancer Research (2023)

Abstract Cytogenetic analysis for hematological malignancies most often includes karyotyping, fluorescence in situ hybridization, and rarely, chromosomal microarray (CMA). While considered the gold standard, karyotyping and FISH have significant limitations in resolution of structural variants (SVs). CMA has a much higher resolution, but cannot detect balanced SVs, and is less commonly used in the hematologic oncology setting. Optical genome mapping (OGM) can detect all classes of SVs at high resolution (duplications, deletions, inversions, insertions, translocations), and as such, detects many copy number variants (CNVs) and SVs that have not been previously described. Although these novel SVs will help better describe genetic contributions to disease, analysis, interpretation and curation can take considerable time. A streamlined workflow has been developed for use with Bionano VIA™ software for a comprehensive analysis of relevant SVs in a hematological malignancy genome. First, by employing disease-specific decision trees for variants published in guidelines for those conditions, the software automatically flags Tier 1A variants detected according to ACMG/AMP/CGC criteria. Second, the overall genome complexity is assessed by observing chromosomal abnormalities detected by OGM. Large events (&amp;gt;5Mb) are counted, and complex genomes are assigned if there are more than 3 or 5 events, depending on the cancer type. Third, calls are further refined by filtering on a pan-cancer specific list to capture those variants that are then manually classified as Tier 1B or 2 by the analyst. The Bionano VIA software allows case-specific and disease subtype-specific information to be added to various sections within the software, such as the Knowledgebase, Event Table, and Sample Info fields to facilitate autopopulation of reportable data and interpretations into a formatted report template. Bionano VIA software can also accommodate multiple platforms simultaneously (e.g., NGS panels) to provide users with a comprehensive view of genomic aberrations relevant to hematological malignancies. This workflow is intended to streamline analysis and automate reporting of oncology samples, which can be extremely complex and often require extensive research. Citation Format: Benjamin Clifford, Jen Hauenstien, Andy Wing Chun Pang, Rachel D. Burnside, Neil Miller, Alex Hastie, Alka Chaubey. Streamlined workflow for analyzing and reporting hematological malignancies in Bionano VIATM software [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2227.
Abstract 3964: APE1 protects SMAD3 against ROC1 ubiquitin mediated degradation in esophageal adenocarcinoma cells
Authors: Farah Ballout, Heng Lu, Dunfa Peng, Wael El-Rifai
Journal: Cancer Research (2023)

Abstract Background: The incidence of esophageal adenocarcinoma (EAC) has increased more than six-fold over the past three decades and continues to rise in the Western world. The 5-year survival rate for EAC patients is less than 20% which underscores the need to better understand the underlying mechanisms to identify new therapeutic approaches. This study aimed at investigating the potential role of APE1 in regulating SMAD3 and promoting EAC progression. Methods and Results: Western blot data showed that APE1 and SMAD3 were highly expressed in EAC cell lines. APE1 silencing reduced SMAD3 nuclear expression and downregulated its downstream targets SERPINE1 and c-myc. These results were confirmed by immunofluorescence staining showing loss of nuclear accumulation of SMAD3 after APE1 knockdown. Mechanistically, immunoprecipitation and proximity ligation assays revealed a direct binding between APE1 and SMAD3 in the nucleus. Further investigation showed that APE1 binds to the C-terminal MH2 domain of SMAD3, and this binding protects SMAD3 from ubiquitin mediated proteasomal degradation by blocking its interaction with the RING finger protein, ROC1. Interestingly, APE1-redox-specific inhibition (APX2009) downregulated SMAD3 expression and the APE1 redox-deficient mutant (C65A) disrupted APE1-SMAD3 binding indicating that this regulation depends on APE1 redox activity. Conclusion: Our findings establish a role of APE1 in regulating SMAD3 in EAC. These findings provide a potential therapeutic approach for the treatment of EAC by the pharmacological inhibition of APE1. Citation Format: Farah Ballout, Heng Lu, Dunfa Peng, Wael El-Rifai. APE1 protects SMAD3 against ROC1 ubiquitin mediated degradation in esophageal adenocarcinoma cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3964.
Abstract 952: Prioritizing mutations associated with smoking as a variable in lung cancer precision medicine with immunotherapies
Authors: Margaret Rose Smith, Yuezhu Wang, Ralph D’Agostino, Yin Lin, Jimmy Ruiz, Thomas Lycan, Umit Topaloglu, Mohammed Abdulhaleem, Michael Chan, Fei Xing
Journal: Cancer Research (2023)

Abstract Background: In 2022, 230,000 new lung cancer cases will be diagnosed in the United States. The treatment regimen for non-small cell lung cancer (NSCLC) has drastically changed owing to the superior anti-cancer effects of immunotherapies. Immune checkpoint inhibitors (ICI) and chemo-immunotherapy (chemo-ICI) are the first-line treatments for NSCLC. Tumor Mutation Burden (TMB) and PD-L1 expression in tumor cells are potential biomarkers in predicting a patient’s survival and response to ICI. However, emerging data have shown that TMB and PD-L1 may no longer be an adequate biomarkers in predicting a patient’s response to ICI or chemo-ICI. We hypothesize that by using tumor-sequencing data and taking into effect a patient’s smoking status, we can identify biomarkers that predict survival to either ICI or chemo-ICI. Methods: To identify biomarkers, we collected genomic sequencing data and comprehensive clinical characteristics on 424 NSCLC patients who received ICI or chemo-ICI treatment at Atrium Health Wake Forest Baptist. Cox-proportional hazard regression models were fit to identify mutations that were “beneficial” (HR &amp;lt; 1) or “detrimental” (HR &amp;gt; 1) for patients on different treatment regimens, followed by the generation of mutation composite scores (MCS) for each treatment. Co-occurrence analysis was performed to identify novel co-occurring and mutually exclusive mutations in each treatment and smoking group by mutation interaction analysis. Results: We identify beneficial and harmful mutations in patients that received ICI or chemo-ICI treatment. We also identified unique biomarkers based on smoking statues. We then created an MCS for each smoking statues group and treatment type to assist personalize treatment. Future directions: We will validate these results in other institute cohorts and add other clinical characteristics to personalize treatment based on MCS for an individual patient. Citation Format: Margaret Rose Smith, Yuezhu Wang, Ralph D’Agostino, Yin Lin, Jimmy Ruiz, Thomas Lycan, Umit Topaloglu, Mohammed Abdulhaleem, Michael Chan, Fei Xing. Prioritizing mutations associated with smoking as a variable in lung cancer precision medicine with immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 952.